IL312038A - Anti-tissue factor antibody-drug conjugates and their use in the treatment of cancer - Google Patents

Anti-tissue factor antibody-drug conjugates and their use in the treatment of cancer

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Publication number
IL312038A
IL312038A IL312038A IL31203824A IL312038A IL 312038 A IL312038 A IL 312038A IL 312038 A IL312038 A IL 312038A IL 31203824 A IL31203824 A IL 31203824A IL 312038 A IL312038 A IL 312038A
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IL
Israel
Prior art keywords
antibody
months
drug conjugate
use according
amino acid
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Application number
IL312038A
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Hebrew (he)
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Genmab As
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Publication date
Application filed by Genmab As filed Critical Genmab As
Publication of IL312038A publication Critical patent/IL312038A/en

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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • C—CHEMISTRY; METALLURGY
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    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

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Claims (15)

1 CLAIMS
1. An antibody-drug conjugate that binds to tissue factor (TF) for use in a method of treating cervical cancer in a subject, wherein the antibody-drug conjugate comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to a monomethyl auristatin or a functional analog thereof or a functional derivative thereof, and wherein the antibody-drug conjugate is administered to the subject once about every 2 weeks at a dose ranging from about 1.5 mg/kg to about 2.1 mg/kg.
2. The antibody-drug conjugate for use according to claim 1, wherein: (a) the dose is about 1.7 mg/kg or about 2.0 mg/kg; (b) the route of administration for the antibody-drug conjugate is intravenous; and/or (c) the antibody-drug conjugate is administered as a monotherapy.
3. The antibody-drug conjugate for use according to claim 1 or 2, wherein the subject has been previously treated with one or more therapeutic agents and: (a) did not respond to the treatment, wherein the one or more therapeutic agents is not the antibody-drug conjugate; (b) relapsed after the treatment, wherein the one or more therapeutic agents is not the antibody-drug conjugate; or (c) experienced disease progression during the treatment, wherein the one or more therapeutic agents is not the antibody-drug conjugate.
4. The antibody-drug conjugate for use according to claim 3, wherein the one or more therapeutic agents: (a) comprises a platinum-based therapeutic agent; or (b) is selected from the group consisting of: paclitaxel, cisplatin, carboplatin, topotecan, gemcitabine, fluorouracil, ixabepilone, imatinib mesylate, docetaxel, gefitinib, paclitaxel, pemetrexed, vinorelbine, doxil, cetuximab, pembrolizumab, nivolumab and bevacizumab. 1
5. The antibody-drug conjugate for use according to any one of claims 1-4, wherein the subject: (a) has experienced disease progression during or after treatment with: i) paclitaxel and cisplatin, ii) paclitaxel and carboplatin, or iii) paclitaxel and topotecan; (b) has received treatment with bevacizumab or is ineligible for treatment with bevacizumab; (c) is not a candidate for curative therapy, optionally wherein the curative therapy comprises radiotherapy and/or exenterative surgery; and/or (d) did not respond to treatment with no more than two prior systemic treatment regimens or wherein the subject relapsed after treatment with no more than two prior systemic treatment regimens.
6. The antibody-drug conjugate for use according to any one of claims 1-5, wherein the cervical cancer is: (a) an adenocarcinoma, an adenosquamous carcinoma or a squamous cell carcinoma; (b) an advanced stage cervical cancer, such as a stage 3 or stage 4 cervical cancer, such as metastatic cervical cancer; and/or (c) recurrent cervical cancer.
7. The antibody-drug conjugate for use according to any one of claims 1-6, wherein: (a) the monomethyl auristatin is monomethyl auristatin E (MMAE); (b) the anti-TF antibody of the antibody-drug conjugate is tisotumab; and/or (c) the antibody-drug conjugate is tisotumab vedotin.
8. The antibody-drug conjugate for use according to claims 1-7, wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate: (a) is a monoclonal antibody or a monoclonal antigen-binding fragment thereof; (b) comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: (i) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:1; (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; and 1 (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO:3; and wherein the light chain variable region comprises: (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6, wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate are defined by the IMGT numbering scheme; (c) comprises a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:8; (d) comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; and/or (e) is tisotumab.
9. The antibody-drug conjugate for use according to any one of claims 1-8, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin, optionally wherein the linker is a cleavable peptide linker, optionally wherein the cleavable peptide linker has a formula: -MC-vc-PAB-, wherein: a) MC is: , b) vc is the dipeptide valine-citrulline, and c) PAB is: . 1
10. The antibody-drug conjugate for use according to claim 9, wherein: (a) the linker is attached to sulphydryl residues of the anti-TF antibody obtained by partial reduction or full reduction of the anti-TF antibody or antigen-binding fragment thereof; optionally wherein the linker is attached to MMAE, wherein the antibody-drug conjugate has the following-structure: wherein p denotes a number from 1 to 8, S represents a sulphydryl residue of the anti-TF antibody, and Ab designates the anti-TF antibody or antigen-binding fragment thereof, optionally wherein the average value of p in a population of the antibody-drug conjugates is about 4; and/or (b) the antibody-drug conjugate is tisotumab vedotin.
11. The antibody-drug conjugate for use according to any one of claims 1-10, wherein at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the cervical cancer cells express TF.
12. The antibody-drug conjugate for use according to any one of claims 1-11, wherein: (a) one or more therapeutic effects in the subject is improved after administration of the antibody-drug conjugate relative to a baseline; optionally wherein the one or more therapeutic effects is selected from the group consisting of: size of a tumor derived from the cervical cancer, objective response rate, duration of response, time to response, progression free survival, and overall survival; (b) the size of a tumor derived from the cervical cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 1 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cervical cancer before administration of the antibody-drug conjugate; (c) the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%; (d) the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the antibody-drug conjugate; (e) the subject exhibits overall survival of at least about 1 month, at least about months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the antibody-drug conjugate; and/or (f) the duration of response to the antibody-drug conjugate is at least about month, at least about 2 months, at least about 3 months, at least about 4 months, at least about months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of the antibody-drug conjugate.
13. The antibody-drug conjugate for use according to any one of claims 1-12, wherein the subject: (a) has one or more adverse events and is further administered an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events; or (b) is at risk of developing one or more adverse events and is further administered an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events. 1
14. The antibody-drug conjugate for use according to claim 13, wherein the one or more adverse events is: (a) anemia, abdominal pain, hypokalemia, hyponatremia, epistaxis, fatigue, nausea, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, vomiting, peripheral neuropathy, or general physical health deterioration; or (b) a grade 3 or greater adverse event; (c) a serious adverse event; or (d) conjunctivitis and/or keratitis and the additional agent is a preservative-free lubricating eye drop, an ocular vasoconstrictor and/or a steroid eye drop.
15. The antibody-drug conjugate for use according to any one of claims 1-14, wherein: (a) the subject is a human; and/or (b) the antibody-drug conjugate is in a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutical acceptable carrier.
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